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Damage from toxins can pass to offspring
By Elizabeth Weise, USA TODAY
6/2/2005
http://www.usatoday.com/news/health/2005-06-02-toxin-offspring_x.htm
Scientists have shown for the first time that exposure to environmental toxins
can cause permanent genetic changes that are passed down through generations.
The research on rats by a team of scientists led by Michael Skinner at
Washington State University in Pullman, Wash., may hold the key to the mystery
of male infertility, which some researchers say has been increasing for unknown
reasons for 20 years.
According to a report in today's edition of the journal Science, Skinner's team
was working with two commonly used chemicals, an insecticide called methoxychlor
and a fungicide called vinclozolin. Both are known to cause infertility in the
male offspring of pregnant animals.
The scientists were looking at the rats and their offspring. But when the
offspring had offspring, the researchers were shocked by what they found in this
second generation. And they were even more surprised by subsequent generations
of the lab rats.
"Lo and behold they had the same" infertility problems, says Skinner, director
of the university's Center for Reproductive Biology.
Not only the grandsons but also the great-grandsons and great-great grandsons of
the exposed mother were similarly affected. The scientists had discovered a
mechanism that permanently changed the reproductive cells.
"That (the changes are) carried down through the generations is what's new and
novel here," says Paul Turek, a male infertility specialist at the University of
California at San Francisco. "Everyone agrees that exposure of the fetus at a
certain critical time can cause malformed organs and birth defects. But no one
ever imagined this might persist at some level for three more generations."
Skinner notes that rat studies cannot necessarily be applied to humans, but he
said the findings warrant a close look at the potential health hazards of
environmental chemicals.
The exposure appears to produce what's called an epigenetic effect, in which a
chemical modification of the DNA in the animal's reproductive cells causes an
alteration with potentially disastrous results — in this case, infertility.
Epigenetic effects are generally erased with each new generation when the cells
that form the sperm or eggs are created in the embryo. But in this case, the
affected genes maintained the alteration and escaped the reprogramming process.
Skinner cautions that the doses used in his research are higher than those
normally found in the environment. He plans to begin testing at lower doses to
see whether the same changes appear.
Human exposure to methoxychlor, which is being phased out in the USA, and
vinclozolin is mostly restricted to agricultural workers, though there's not
much data to go on, Skinner says. He expects that other researchers will now
begin looking for similar effects in people.
But "to the extent that it's been studied, the epigenetic effects seen in
rodents are similar to those seen in humans," says John McCarrey, an expert on
epigenetics at the University of Texas at San Antonio.
The findings may one day facilitate new diagnostic approaches and therapies,
Skinner says. For example, doctors would be on the lookout much earlier for
certain diseases if they knew that their patients' ancestors had been exposed to
certain toxins, he says.
Environmental Toxicants Like Lead, Mercury Target Stem Cells
07 Feb 2007
Low levels of toxic substances cause critical stem cells in the central
nervous system to prematurely shut down. That is the conclusion of a study
published in the on-line journal PLoS Biology. This research, which
is the first to identify a common molecular trigger for the effects of
toxicant exposure, may give scientists new insights into damage caused by
toxicant exposure and new methods of evaluating the safety of chemicals.
While scientists have long understood that certain chemicals like lead and
mercury have adverse effects on the body, the precise molecular mechanism by
which many of these substances cause harm remain uncertain. This makes it
more difficult to concretely link individual toxic substances with specific
diseases or determine - with greater confidence - whether or not a chemical
is toxic. However, recent advances in molecular biology, genetics, and stem
cell biology have provided scientists a new window onto the impact of toxic
substances on the cellular and molecular level.
"Establishing the general principles underlying the effects of toxicant
exposure on the body is one of the central challenges of toxicology
research," said University of Rochester biomedical geneticist Mark Noble,
Ph.D., senior author of the study. "We have discovered a previously
unrecognized regulatory pathway on which chemically diverse toxicants
converge and disrupt normal cell function."
Noble and his colleagues exposed a specific population of brain cells to low
levels of lead, mercury, and paraquat, one of the most widely used
herbicides in the world. These cells, called glial progenitors, are
advanced-stage stem cells that are critical to the growth, development, and
normal function of the central nervous system. The activity of cells is
regulated by molecular pathways - or controlled chemical reactions -
normally set off when substances bind to receptors on the cell's surface.
Noble and his colleagues found that these compounds turned off specific sets
of receptors and set into motion a molecular chain reaction that causes the
cells to shut down and stop dividing.
"These toxicants are activating a normal cellular regulatory pathway, they
are just activating it inappropriately," said Noble. "If this disruption
occurs during critical developmental periods, like fetal growth or early
childhood, it can have a significant impact. Development is a cumulative
process, and the effects of even small changes in progenitor cell division
and differentiation over multiple generations could have a substantial
effect on an organism."
This study is an example of the ability of stem cell research to shed new
light on many diseases and health problems that have heretofore been poorly
understood by the medical community. Noble and his colleagues are pioneers
in the field and have been involved in the discovery of several of the
progenitor cells that are involved in building the central nervous system.
The growing knowledge of the precise timing and role of these cells has
enabled scientists to explore the molecular origin of these diseases, and
the Rochester team's findings are part of a growing number of discoveries
that indicate that certain developmental syndromes may be the result of
disruption in stem cell function.
There are tens of thousands of synthetic industrial chemicals, pesticides,
metals, and other substances for which toxicological information is limited
or nonexistent. By identifying a molecular target that is shared by toxic
substances, all with very different chemical compositions, this discovery
may give scientists a method to rapidly evaluate compounds to determine
whether or not they pose a potential health threat.
"One of the obstacles in the analysis of new chemicals is the difficulty in
developing a system that is sensitive enough and can make predictions that
are true for both individual cells and the entire organism," said Noble.
"This novel pathway gives as a way to analyze a diverse array of chemicals
at levels in which they would be encountered in the environment.
Furthermore, by identifying a specific molecular pathway that is activated
by toxic exposure, we can now begin to look at specific ways to protect
cells from this disruption of signaling."
Funding for the research came from National Institute of Environmental
Health Sciences. Other investigators participating in the study were lead
author Zaibo Li, M.D., Ph.D., Tiefei Dong, Ph.D., and Chris Proschel, Ph.D.,
all with the University of Rochester Medical Center.
Contact: Mark Michaud
University of
Rochester Medical Center
Article URL: http://www.medicalnewstoday.com/medicalnews.php?newsid=62421 |
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